醋酸奥曲肽微球的制备及工艺优化

81Vol.8No.120101ChineseJournalofPharmaceuticsJan.2010p.1:20090525:(1983),(),,,[e-mail];(1962),(),,,,Tel.[phone],[e-mail](2010)010001081222211.1100162.102206W/O/W1.8mL1.64%1.2%51.74µm1.585.50%88.00%79.02%9.19%R94Aoctreotide,12h23min30Sandostatin®3SandostatinLAR®Depot1[1][2][3][4]1T25IKAOJ60()XSP8CASHABLC2010AHT2800B080101PLGARESOMER®RG503H50:500.320.44d•g-130000BoehringerIngelheim488FlukaDimaTechnology28ManufacturedSKChemicals22.1W/O/WPLGA200mg()W/OW/O/W4h10µm38h125µm[5-6]2.22.2.1E200spanspan=d90d10/d50d10d50d9010%50%90%2.2.2HPLCAgilentC184.6mm×150mm5µmA0.1%B0.1%B12min25%35%4min205nm1.0mL·min-112510204080120160mg·L-1HPLCρAA=5.4057104ρ4.2546104r=0.99991160mg·L-11.90%n=625mg10mL2.5g·L-1160200240µL310mg1.5mL4.5mL99.65±0.030%98.96±0.84%98.39±0.78%10mg1.5mL4.5mL5min10000r•min-110min20µLHPLC[7]=/×100%=/×100%2.2.320mg15mLpH7.40.02%NaN3130.02%Tween804mL37±0.5100r•min-1124612181430d4000r•min-110min[8]HPLC12.32.3.13X1mLX2%X3%51Y1µmY2Y3w)Y4w)Y5w)Y6w)DesignExpert®7.1.4202Table1VariablesandcodesofthecentralcompositedesignLevelcodeFactorα101+αX11.201.401.702.002.20X21.161.502.002.502.84X30.160.501.01.501.84Table2ResultsofthecentralcompositedesignFormulationvariablesResponseNoX1X2X3Y1Y2Y3Y4Y5Y611.401.500.5090.541.145.5188.1673.431.8722.002.500.5033.71.144.8777.9268.8112.7331.402.501.5046.381.935.3685.7678.186.441.702.001.0052.051.205.7191.3675.189.7752.001.501.5050.291.535.4587.2077.9311.3261.702.001.0042.162.215.4787.5274.759.5371.702.001.0039.931.855.6690.5671.876.5482.001.500.5048.411.715.1181.7684.618.0691.401.501.5070.32.095.2984.6482.993.84101.402.500.5029.72.55.3285.1277.815.34111.702.001.0036.711.755.5789.1277.819.41122.002.501.5035.111.235.5088.0069.6222.11131.702.001.8437.432.455.1281.9274.9310.04(tobecontinued)48Continuedtable2141.702.001.0043.761.875.6890.8877.8111.57152.202.001.0042.541.385.0580.8072.1217.29161.702.851.0032.981.334.7876.4870.7515.08171.702.001.0038.591.55.6089.6071.0018.01181.202.001.0044.832.674.7876.4870.7511.04191.701.161.0058.451.555.1782.7274.686.44201.702.000.1654.011.745.0180.1671.873.982.3.2DesignExpert®7.1.4Y1=46.655.36X111.53X22.06X3P=0.0019,R=0.8025Y2=3.492940.31X12.929×10-3X2(P=0.0370,R=0.5963)Y3=5.617.023×10-3X17.1×10-2X2+.7.1×10-2X38.750×10-3X1X2+4.0×10-2X1X30.17X12+0.15X220.12X32P=0.0318,R=0.8780Y4=89.780.11X11.13X2+1.14X30.14X1X2+2.30X1X32.70X12-2.36X221.85X32(P=0.0318,R=0.8780)Y5=75.050.67X12.28X2+0.67X32.96X1X21.98X1X30.21X2X3(P=0.0321,R=0.8134)Y6=9.83+3.46X1+2.64X2+1.89X3(P=0.0015,R=0.8104)2.3.3DesignExpert®7.1.4[9]115AMeandiameterasafunctionofX1andX3;BSpanasafunctionofX1andX3;CEncapsulationefficiencyasafunctionofX1andX3;DYieldasafunctionofX1andX2;EInitialreleaseasafunctionofX1andX2;FDesirabilityasafunctionofX1andX2Fig.1ResponsesurfaceplotsPLGA683[10]PLGAPLGA2.41.80mL1.64%1.20%323Table3ComparisonoftheobservedandpredictedvaluesofthemicrospherespreparedunderoptimizedconditionsIndexofmicrospheresPredictedresponseObservedresponseBiasadmean/µm52.3951.741.24Span1.631.583.07wdrug/%5.595.501.61wencapsulationefficiency/%89.5088.001.68wyield/%77.2979.022.24winitialrelease/%9.869.196.80aBias=predictedresponseobservedresponse/observedresponse×100%17Fig.2ScanningelectronmicrographofoctreotideacetatemicrospheresFig.3ReleasecurveofoctreotideacetatefromPLGAmicrospheresinvitro377.00%24h9.19%30d88.49%[1]HUNTERSJ,SHAWJA,LEEKO,etal.ComparisonofmonthlyintramuscularinjectionsofsandostatinLARwithmultiplesubcutaneousinjectionsofoctreotideinthetreatmentofacromegaly:Effectsongrowthhormoneandothermarkersofgrowthhormonesecretion[J].ClinEndocrinol(Oxf),1999,50(2):245251.[2]KUTZK,NUESCHE,ROSENTHALERJ.PharmacokineticsofSMS201-995inhealthysubjects[J].Gastroenterol,1986,21(1):(6572).[3],.[J].,2002,27(5):292298.[4]ABU-IZZRKA,GARCIA-CONTRERASL,LUDR.Preparationandevaluationofzidovudine-loadedsustatinedreleasemicrospheresoptimizationofmultipleresponsevariable[J].PharmSci,1996,85(6):572576.88[5]JEYANTHIR,THANOOBC,MEHTARC,etal.Effectofsolventremovaltechniqueonthematrixcharacteristicsofpolylactide/glycolidemicrospheresforpeptidedelivery[J].JControlRelease,1996,38(2):235244.[6]JEYANTHIR,MEHTARC,THANOOBC,etal.Effectofprocessingparametersonthepropertiesofpeptide-containingPLGAmicrospheres[J].Microencapsul,1997,14(2):163174.[7]BODMERD,KISSELT,TRAECHSLINE.Factorsinfluencingthereleaseofpeptidesandproteinsfrombiodegradableparenteraldepotsystems[J].ControlledRelease,1992,21(27):129138.[8]YANGJ,CELANDJL.Factorsaffectingtheinvitroreleaseofrecombinanthumaninterferon-gamma(rhIFM-gamma)fromPLGAmicrospheres[J].JPharmSci,1997,86(8):908914.[9],.[J].,2008,16(3):175178.[10],.[J].:,2006,33(3):219223.Preparationofoctreotideacetateloadedpoly(lactic-co-glycolicacid)microspheresandoptimizationoftheformulationLENGDi1,PENGBo2,WANGYi-fei2,LIUJin-ai2,WANGMing-xin2,WANGDong-kai1(1.SchoolofPharmacyShenyangPharmaceuticalUniversityShenyang110016China2.TheNationalInstitutesofPharmaceuticalR&DCo.,Ltd,Beijing102206ChinaAbstract:ObjectiveTooptimizetheformulationofoctreotideacetateloadedpoly(lactic-co-glycolica